Ets proteins are transcription factors, which share a unique DNA binding domain, the Ets domain. Some members of the Ets family are implicated in tumorigenesis. Ets1, the founder of the Ets family, is predominantly expressed in invasive tumors and able to activate certain genes encoding ECM-degrading proteases. We used RNA-interference in combination with DNA chip analysis to identify Ets1-regulated genes in MDA-MB-231 breast cancer cells. Of the Ets1-responsive proteases, matrix metalloproteases MMP1 and MMP9, but not MMP3 or uPA, showed reduced RNA levels when endogenous Ets1 expression was suppressed. These data suggest that Ets1 regulates only a certain subset of ECM-degrading proteases. How Ets1 is regulated in invasive breast cancer cells is unknown. The observations that protein kinase C inhibitors abrogated Ets1 expression and that protein kinase C was able to increase Ets1-dependent transcription imply that protein kinase C is a potential regulator of Ets1 activity in breast cancer cells.
e21022 Background: We measured CTC s and MST of MBC [ER+, HER2- (HR+); HER2+ (H2+); or Triple Negative (TN)] in all MBC pts in our practice and used these in an algorithm to treat MBC. Methods: CTC’s were measured in 156 pts whether beginning Rx with 1st MBC (97), or under way with Rx (59). Pts had CTC s measured over 61 mo. from 11/20/06 thr. 12/31/11; 66 of the pts had died as of 12/31/11. Pts were Rx’d with an algorithm using CTC’s and MST: Pts with ≥ 5 CTC s were Rx’d with chemoRx, usually doublet ChemoRx, but accounting for pt preferences. When CTC’s improved to < 5 for a sustained 3-4 mo. period, or if initially < 5m we sought less morbid therapies: hormonal if ER+, or single agent ChemoRx +/- biologics if ER- or hormone refractory. In a detailed statistical analysis of variables affecting Disease Specific Survival (DSS) in the first 140 pts thr. 6/30/11, with median f/u of 24.0 mo., highest CTC level (max CTC) observed during f/u was used for analysis: CTC Low (max <5, n=60); CTC Moderate (max 5-99; n=55); and CTC High (max ≥ 100; n=25). Results: We reported the distribution of pts and death rates for the 3 MST and the 3 max CTC groupings earlier (Graham, ASCO 2010); the conclusions are similar with 156 pts and longer f/u. Each MST has 40% of pts with 0-4 CTC’s at all time points. Each MST has a smaller group with CTC’s ≥ 100, 16% of all pts. 33% of deaths (22 of 66) occurred in the ≥ 100 CTC pts. 88% with ≥ 100 CTC’s died; these are early deaths. Only 13 of 66 (20%) died if CTC’s < 5, and 31 of 65 (48%) ifh 5-99 CTC’s. In the first 140 pt analyzed thr. 6/30/11, the median DSS from date of highest CTC is not reached for the CTC Low (max. f/u 54 mo.), vs. 35.8 mo. in the CTC Moderate and 3.3 mo. in the CTC High. DSS was signif. longer for the CTC Low and CTC Moderate vs. the CTC High (P<0.001 for both comparisons). DSS was also signif. greater in the CTC Low vs. the CTC Moderate (P = 0.04). Cox multivariate analysis showed that the Max CTC group (HR 4.8, 95% CI 3.1 - 7.6, p < 0.001), age ≥ 55 at time of max CTC (HR 4.0, 95% CI 2.7 - 7.9, p < 0.001), and MST (HR 2.1, 95% CI 1.4 – 3.1, p < 0.001) were predictive of DSS. Conclusions: a. A treatment algorithm of CTC’s and MST in MBC finds subgroups of MBC with long, intermediate and very short DSS; b. Effective treatments are short-lived in pts with CTC max ≥ 100.
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